An Efficient One-Pot, Three-Component Reaction: Synthesis of Complex-Annelated α-Carbolines via an Intramolecular [3+2]-Dipolar Cycloaddition Reaction

Abstract

Novel annelated α-carbolines have been synthesized from oxindole using three components in a one-pot procedure involving an intramolecular [3+2]-dipolar cycloaddition reaction of azides to nitriles.

Key words

α-carboline - oxindole - [3+2]-dipolar cycloaddition reaction - β-halo aldehyde - multicomponent reaction

References and Notes

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19

General Procedure for Three-Component Reaction To a mixture of 1-Boc-2-chloro-3-formylindole (3a, 279 mg, 1 mmol), ethyl cyanoacetate (4a, 170 mg, 1.5 mmol), and NaN₃ (5, 80 mg, 1.24 mmol) in DMF (5 mL) were added 2 drops of H₂O. A catalytic amount (1-2 drops) of Et₃N was then added, and the reaction mixture allowed to stir for 3 h at 50-60 ˚C. After completion of the reaction, the mixture was cooled to r.t. and poured into H₂O with continuous stirring. A yellow-brownish solid product was formed after keeping the mixture inside the freezer overnight. Product 6a was purified by preparative TLC using EtOAc-hexane (3:7).
Compound 6a
Yield 270 mg (71%); mp 221-223 ˚C. ^¹H NMR (300 MHz, CDCl₃): δ = 1.25 (t, J = 7.07 Hz, 3 H), 1.72 (s, 9 H), 4.17-4.23 (m, 2 H), 7.20-7.86 (m, 3 H), 8.18 (s, 1 H), 8.57-8.63 (m, 1 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 14.23, 28.08, 62.20, 86.81, 105.09, 113.52, 115.22, 115.66, 121.09, 124.08, 124.40, 125.77, 130.83, 135.66, 146.37, 147.89, 162.57. MS (EI): m/z = 382.4 [M + H]⁺. Anal. Calcd (%) for C₁₉H₁₉N₅O₄: C, 59.84; H, 4.98; N, 18.37. Found: C, 59.65; H, 4.93; N, 18.42. IR (CHCl₃): ν_max = 2983.00, 2856.50, 1751.90, 1728.10 cm^-¹. Similar compounds 6b-i were synthesized and characterized.

20

Synthesis of Compound 3a
Equimolar amounts of 2-chloro-3-formyl indole (2, 10 mmol, 1.79 g) and Boc-anhydride (10 mmol, 2.18 g) were stirred in the presence of catalytic amount of DMAP (0.12 g) and Et₃N (0.10 g) at 0-5 ˚C for 1 h using CH₂Cl₂ as solvent. The solvent was evaporated under reduced pressure, and the solid compound obtained was purified by column chromatography using PE-EtOAc (9:1) as eluent. The product 3 was obtained in 70% yield (1.20 g) as white crystalline compound; mp 89-90 ˚C. ^¹H NMR (300 MHz, CDCl₃): δ = 1.72 (s, 9 H), 7.26-7.40 (m, 2 H), 8.02-8.06 (m, 1 H), 8.27-8.30 (m, 1 H), 10.29 (s, 1 H).
Synthesis of Compound 3b
2-Chloro-3-formyl-indole (2, 1.78 g, 10 mmol) was taken in a round-bottom flask in DMF (10 mL) on magnetic stirrer. NaH (0.48 g, 20 mmol) was added into the mixture. When the temperature reached 0 ˚C, MeI (1.42 g, 10 mmol) was added gradually, and the reaction mixture allowed to stir for 1.5 h. An off-white solid formed which was almost pure product. Yield 1.59 g (82%); mp 79-80 ˚C. ^¹H NMR (300 MHz, CDCl₃): δ = 3.80 (s, 3 H), 7.20-8.30 (m, 4 H), 10.12 (s, 1 H).
Synthesis of Compound 3c
2-Chloro-3-formyl-indole (2, 1.78 g, 10 mmol) was refluxed with allyl bromide(10 mmol) in the presence of K₂CO₃ (10 mmol) using acetone (10 mL) as solvent for 10 h to afford 3c, 1.69 g (76%) as a colorless solid, mp 148-149 ˚C. ^¹H NMR (300 MHz, CDCl₃): δ = 4.80 (d, J = 11.4 Hz, 2 H), 5.10-5.27 (d, J = 10.2 Hz, 2 H), 5.95-6.07 (m, 1 H), 7.20-8.26 (m, 4 H), 10.16 (s, 1 H).

21

Synthesis of Compound [A] 1-Boc-2-chloro-3-formylindole (3a, 558 mg, 2 mmol) was treated with ethyl cyanoacetate (4a, 283 mg, 2.5 mmol) in EtOH (8 mL). One drop of piperidine was added, and the reaction mixture was allowed to stir at r.t. for 30 min. The reaction mixture was kept inside the freezer overnight. The yellow solid which appeared in the reaction mixture was filtered, washed with cold EtOH and dried. Yield 508 mg (75%); mp 87-88 ˚C. ^¹H NMR (300 MHz, CDCl₃): δ = 1.43 (t, J = 3.6 Hz, 2 H), 1.72 (s, 9 H), 4.36-4.44 (m, 2 H), 7.20-8.10 (m, 4 H), 8.49 (s, 1 H).

22

Synthesis of α-Carboline 6a from [A] The condensed product [A] (339 mg, 1 mmol) was mixed with NaN₃ (5, 80 mg, 1.24 mmol) in DMF (5 mL) and 2 drops of H₂O were added. A catalytic amount (1-2 drops) of Et₃N was then added to the reaction mixture, and the whole was stirred for 3 h at 50-60 ˚C After completion of reaction, the mixture was cooled to r.t. and poured into H₂O with stirring. A yellow-brownish solid was formed after keeping the mixture inside the freezer overnight. Product 6a was purified by preparative TLC using EtOAc-hexane (3:7); yield 251 mg (66%); mp 221-223 ˚C.